123 PROJECT SUMMARY/ABSTRACT 456 The need for longitudinal follow-up of individuals exposed to interventions against rare infectious disease endpoints poses a barrier to prospective efficacy and effectiveness studies. Studies using the test-negative design (TND) have become a popular alternative. TNDs 78 represent a variant on traditional case-control designs: studies enroll subjects who seek care for a clinical syndrome, defining those who test positive and negative for a pathogen of interest as 109 ?cases? and ?controls?, respectively. To facilitate rigorous and reproducible assessments of vaccine performance, the project will re-assess emerging applications of the TND, and 1112 contribute methods to measure intervention effects from data collected by TND studies. 1134 The first two aims revisit estimation strategies for vaccine-conferred protection against infection and against the progression of infection to disease?the two components of the vaccine ?direct 1156 effect? that TND studies aim to measure. We propose novel frameworks to estimate each effect through extensions of the TND: one through comparisons of symptomatic and asymptomatic 111789 persons, and another leveraging the age distribution of cases. We will apply these methods to estimate pneumococcal conjugate vaccine effectiveness against vaccine-serotype pneumococcal pneumonia and carriage, and to re-assess reported differences in rotavirus vaccine effectiveness 2201 across high, middle, and low-income countries. 2223 In Aim 3, we will continue development of statistical procedures for cluster randomized test- negative designs. A major field trial of this nature for a vector intervention utilizing the 2245 bacterium Wolbachia to reduce dengue fever transmission is nearing completion. Permutation- based inference is planned because of small numbers of clusters. We will extend such methods 2267 (i) to allow for individual measures of intervention exposure (based on human and mosquito mobility), and (ii) to include design variants such as the stepped wedge design and interrupted 2289 time series where data collection has either recently ended or is in process. We will also consider a novel application to assess a new vaccine against Ebola Virus Disease (EVD) in the 30 Democratic Republic of the Congo. This project will thus contribute methods and computational routines to allow valid inferences from TND study data, permitting novel assessments of interventions against rotavirus, pneumococcal disease, EVD, and dengue etc.